The introduction of potent direct acting antivirals (DAA) has significantly improved the treatment response of patients with chronic HCV infection. However, at present, these interferon (IFN)-free treatment regimens are not available for most patients worldwide, partly due to the high costs. The WHO estimates IFN-based therapy will remain the sole available therapy particularly middle and low-income countries for the next several years. In addition, IFN remains important for HCV genotype 3 infected patients as part of a combination therapy with DAAs. The response rate to IFN-based therapy is negatively influenced by the pre-activation state of the innate immune response, which has a genetic component. At present, it is not known whether the responsiveness to IFN-based therapy can be improved. We have now completed and published a study that shows that rapid reduction in viremia within the first 24 hours of therapy with DAAs improves the IFN response of patients who had failed a standard course of pegylated IFN (PegIFN)/ribavirin (RBV) therapy in the past. We used NK cell phenotype and function as biomarker for IFN-responsiveness, because chronic exposure to low levels of HCV-induced endogenous IFN induces the ISGs STAT1 and TRAIL in NK cells, and enhances their cytotoxicity. We show that the 24h-virological response to therapy with PegIFN/RBV/DAAs correlated with an increase in pSTAT1 and STAT1 expression in NK cells, which was greater than during the previous unsuccessful course of PegIFN/RBV therapy. This was associated with an increase in NK cell function as measured by increased TRAIL secretion and expression of the degranulation marker CD107a that serves as a readout for cytotoxicity. In a follow up study, we asked whether the NK cell phenotype pre-treatment and at early treatment time points differs between HCV genotype 1b-infected patients who develop a sustained virological response (SVR) to DAA-based therapy (asunaprevir/daclatasvir or sofosbuvir/ledipasvir) and those who experience a virological breakthrough. Before treatment, patients who achieved an SVR had a higher percentage of pSTAT1 and TRAIL-expressing NK cells than those who developed a virological breakthrough. This was accompanied by a higher frequency of degranulating NK cells in response to target cells. Further, pre-treatment plasma CXCL10 levels were higher in patients with SVR, indicating a more prominent HCV-induced IFN- effect in this patient group. These results suggest the relevance of an endogenous IFN response in preventing breakthrough.